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Association between cerebrospinal fluid metabolites and ischemic stroke: a Mendelian randomization analysis
Zhen Wei1, Chunshu Rong2, Qiyi Ta3
1Medical Intensive Care Unit, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130021, Jilin, China.
Journal of Thrombosis and Thrombolysis
|May 27, 2026
Summary
This study reveals 23 cerebrospinal fluid (CSF) metabolites causally linked to ischemic stroke (IS) prognosis. Deoxyuridine shows potential as a biomarker for predicting IS outcomes, offering new insights into stroke mechanisms and interventions.
Area of Science:
- Neuroscience and Neurology
- Metabolomics and Biochemistry
- Genetics and Epidemiology
Background:
- Ischemic stroke (IS) is a major global cause of disability and mortality.
- Cerebrospinal fluid (CSF) metabolites may reflect central nervous system pathophysiology but their causal link to IS prognosis is unclear.
- Understanding these relationships is crucial for developing novel therapeutic and diagnostic strategies.
Purpose of the Study:
- To investigate the causal association between CSF metabolites and IS prognosis.
- To identify potential CSF metabolite biomarkers for predicting IS outcomes.
- To explore the underlying mechanisms linking CSF metabolites to IS progression.
Main Methods:
- Employed a two-sample Mendelian randomization (MR) design using genetic data for 338 CSF metabolites and IS prognosis data from 6021 patients.
- Selected instrumental variables based on stringent statistical criteria and excluded potential confounders.
- Utilized inverse variance weighted (IVW) method for causal estimates, with comprehensive sensitivity analyses including MR-Egger and MR-PRESSO. Performed metabolomic validation, ROC analysis, and KEGG enrichment analysis.
Main Results:
- Identified 23 CSF metabolites with a significant causal association with IS prognosis: 18 protective and 5 risk metabolites.
- Deoxyuridine demonstrated high predictive power (AUC=0.944) and overlapped with metabolomic validation results.
- Sensitivity analyses confirmed the robustness of findings, with no significant heterogeneity or pleiotropy detected. KEGG analysis suggested involvement in autophagy and AMPK signaling pathways.
Conclusions:
- This is the first study to systematically establish causal links between specific CSF metabolites and IS prognosis.
- Identified risk metabolites (e.g., cholesterol, phenylalanine) and protective metabolites (e.g., deoxyuridine, sphingolipids) offer insights into IS mechanisms like atherosclerosis and neuroinflammation.
- Deoxyuridine emerges as a promising biomarker for IS outcome prediction, potentially guiding early intervention strategies.
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Ischemic stroke is an acute cerebrovascular condition in which blood flow to a brain region is suddenly interrupted, leading to tissue infarction. Neurons depend on continuous oxygen and glucose supply, so even brief reductions in perfusion cause energy failure, ionic imbalance, and irreversible injury. Ischemic strokes are classified into thrombotic and embolic types based on their underlying mechanisms.Thrombotic MechanismsThrombotic stroke develops when a clot forms within a cerebral artery.
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